Human natural killer (NK) cells are capable of spontaneously killing certain tumor and virus-infected cells. In addition, NK cells can kill IgG antibody-coated target cells via antibody- dependent cellular cytotoxicity (ADCC) and it is the Fc portion of the IgG binding to an Fc receptor (FcgammaR) on the surface of the NK cell that provides the signal for the activation of the lytic machinery. Almost all NK cells express FcgammaRIII, and this receptor has been shown to be involved in NK cell-mediated ADCC. Until recently this was thought to be the only FcgammaR expressed on NK cells. However, we have recently shown that NK cells, from certain individuals, also express high levels of FcgammaRII, and found these to be products of the FcgammaRIIC gene, an isoform that has not been well characterized in any cell. We have further shown that an allelic polymorphism of aa 13 in the first extracellular (EC1) domain results in individuals whose NK cells are CD32neg or CD32pos. This molecule, when expressed on NK cells, can trigger ADCC and increases in intracellular CA+2 flux. In addition, using Jurkat cells transfected with two FcgammaRIIc isoforms we have defined the ligand binding specificity and signal transduction pathway of these FcgammaRs. These studies are of potential significance because NK cells have not been previously shown to express CD32 and thus this potentially represents a new means of activating and/or regulating NK cell lysis. Based on these data we hypothesize that the presence of high levels of FcgammaRII expression on NK cells of some individuals influences the function of their NK cells by activating and/or regulating the lytic and immunoregulatory function of NK cells. The present proposal is aimed at determining the functional significance of the novel CD32 isoforms expressed by human NK cells and to test our hypothesis, by assessing their role in NK cell functions. The specific aims of the proposal are: 1) To determine the functional significance of novel CD32 isoforms in normal NK cells; 2. To determine the role of MHC class I-specific inhibitory receptors in the modulation of functions mediated by CD32; 3) To assess the possible differences in ADCC activity of NK cells against tumor targets from CD32pos or CD32neg individuals.